1. Technical Field
The disclosure relates to a method of making, preventing, and reversing pathologic vessel condition and new vessel growth.
2. Background Art
Neovascularization, or angiogenesis, is the pathological new vessel growth. These conditions characterized by abnormal neovascularization, include diabetic retinopathy, glaucoma secondary to rubeosis iridio, rheumatoid arthritis, and certain solid cancers. For example, diabetic retinopathy is the leading cause of blindness among working age adults in the United States. Microaneurysms are early signs. Such lesions may be associated with hypertension or AIDS, but most commonly with diabetes. Effects on the kidneys may be indicated by the development of albuminuria, and the effects on the peripheral nervous system by diminished perception of hot or cold, but effects of microaneurysm and hemorrhage on retina may threaten man's vision even before other symptoms could happen (Klein, R and Klein B E K: Diabetic Eye Disease, The Lancet, Vol 350, p197-204, July, 1997). A subset of patients with age related macular degeneration develops subretinal neovascularization, which eventually leads to blindness.
Much research has been focused on preventing the formation of the Diabetic Retinopathy prior to blindness. Several models have been used for the study of diabetic retinopathy, helping a better understanding of the process involved. A major problem of angiogenesis, e.g., diabetic retinopathy, is the hardship of making and treating the progressive behavior of neovascularization.
Streptozotocin treatment is used to affect the pancreatic beta cells, rapidly reducing them until insulin is no longer synthesized in sufficient amounts. The galactosemic model shifts metabolism away from glucose, increasing aldose reductase and retinal polyol metabolism. Finally, two weeks of cycled oxygen from high to low tension every 24 hours, followed by return to room air triggers microangiogenesis in developing retina. Use of these models, separately or in combination, as well as electroretinographic analysis, has begun to reveal the events taking place as diabetic retinopathy progresses. Endothelial cells become separated from pericytes as basement membranes thicken, and vascular endothelial growth factor increases, triggering their proliferation (Bazan N G et al.: Experimental Models and Their Use in Studies of Diabetic Retinal Microangiopathy, Therapie, 52(5): 447-51, 1997 Sep-Oct.). Human neovascularization studies are limited by the inaccessibility of the affected tissues. (Pfeiffer, A. et al: Growth Factor Alterations in Advanced Diabetic Retinopathy: A Possible Role of Blood Retina Barrier Breakdown, Diabetes 46, Suppl 2: S26-S30, 1997). Much research has focused on the galactosemic model of dog eyes. Simulating human diabetic retinopathy angiogenesis and observing the unique human retinal neovascularization progress have been a long existing unsolved problem (Eastman, R C et al.: Model of Complications of NIDDM. 1. Model construction and assumptions, Diabetes Care, 20(5), pp 725-734, May 1997) (Kern T S & Engerman R L: Capillary lesion develop in retinal rather than cerebral cortex in diabetes and experimental galactosemia, Achives of Ophthalmology, 114(3): 306-310, March, 1996).
Also, most cancers can't grow bigger than one to two mm diameter if there is no angiogenesis. It would be desirable to test and identify antiangiogenesis agents useful in treating the foregoing diseases on animals who can host human angiogenesis. This method provides human xenograft neovascularization for exploring the mechanism of angiogenesis and prompt response of pharmaceutical testing.